Journal of the Neurological Sciences 355 (2015) 64–67
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Longitudinal ultra-extensive transverse myelitis as a manifestation of neurosarcoidosis Lei Wang a, Yuebing Li b,⁎ a b
Department of Neurology, Second Artillery General Hospital, Beijing 100088, China Department of Neurology, Cleveland Clinic, Cleveland, OH 44195, USA
a r t i c l e
i n f o
Article history: Received 9 March 2015 Received in revised form 19 April 2015 Accepted 12 May 2015 Available online 22 May 2015 Keywords: Sarcoidosis Neurosarcoidosis Spinal cord sarcoidosis Myelopathy Transverse myelitis Immunosuppression
a b s t r a c t Objective: To analyze the clinical characteristics and outcome of patients with neurosarcoidosis manifesting as longitudinal transverse myelitis spanning 6 or more spinal segments. Method: Retrospective analysis of 7 cases from a single institution. Results: Four males and 5 African–American were included. The mean onset age for neurological symptoms was 49.1 years old. Only 1 patient had a prior diagnosis of sarcoidosis. In all patients, spinal MRI showed contiguous cervical and/or thoracic cord lesions predominantly in a central or centrodorsal location, associated with parenchymal or leptomeningeal gadolinium enhancement. Cerebral spinal fluid (CSF) pleocytosis was present in all and hypoglycorrhachia in 3 patients. Angiotensin-converting enzyme (ACE) level was elevated in the serum of 1 patient while being normal in the CSF of all 4 cases tested. Chest imaging facilitated the diagnosis of sarcoidosis in all cases. The use of corticosteroid and immunosuppressive agents including infliximab and methotrexate led to improved outcome. Conclusions: Neurosarcoidosis should be considered in the differential diagnosis of longitudinal ultra-extensive myelitis, even in the absence of previously diagnosed sarcoidosis. Timely usage of corticosteroid and immunosuppressive agents improves the clinical outcome of patients with ultra-extensive spinal cord sarcoidosis. © 2015 Elsevier B.V. All rights reserved.
1. Background Sarcoidosis is a multi-system granulomatous disorder which often affects lung, skin, liver, bone marrow and nervous system. The incidence of nervous system involvement in sarcoidosis is approximately 5 to 15% [1]. Spinal cord sarcoidosis is very rare, occurring in less than 1% of all sarcoidosis patients [2]. Longitudinal extensive transverse myelitis, defined as spinal cord inflammatory lesions extending longitudinally over 3 or more vertebral segments, was rarely reported in neurosarcoidosis [3–5]. In this study, we describe a group of 7 patients who demonstrated reversible myelitis affecting 6 or more contiguous spinal segments, termed here longitudinal ultra-extensive transverse myelitis (LUTM), as a manifestation of neurosarcoidosis.
findings, biopsy results, treatment regimens and clinical outcome. Data were expressed as mean, standard deviation and range. Percentages of positive and negative findings were calculated. No statistical analysis was needed. Positive diagnosis of transverse myelitis was confirmed using previously published criteria [6]. Acute onset was defined as neurological deficit reaching its peak within 1 month, while subacute onset between 1 and 3 months and chronic onset after 3 months or with a progressive course. Duration of follow-up included time between first and most recent neurological assessments. 3. Results 3.1. Patient demographics
2. Methods The study was approved by the Cleveland Clinic Institutional Review Board. Seven patients were included in the study. Data from electronic medical records were collected, including demographics (gender, race and onset age), symptoms and signs, laboratory and radiological
Three patients (42.9%) were female and 5 (71.4%) African American. The mean age at the onset of neurological symptoms was 49.1 ± 9.4 years (range: 39 to 63 years). The mean follow-up duration was 55.6 months (range: 6 to 123 months).The clinical summary for all 7 patients is outlined in Table 1. 3.2. Clinical presentation
⁎ Corresponding author at: Department of Neurology, Cleveland Clinic, 9500 Euclid Avenue, S90, Cleveland, OH 44195, USA. Tel.: +1 216 445 9525; fax: +1 216 445 4653. E-mail address: [email protected] (Y. Li).
http://dx.doi.org/10.1016/j.jns.2015.05.017 0022-510X/© 2015 Elsevier B.V. All rights reserved.
Chest imaging revealed pulmonary involvement in all 7 patients, manifesting predominantly as hilar and/or mediastinal node enlargement.
L. Wang, Y. Li / Journal of the Neurological Sciences 355 (2015) 64–67
65
Table 1 Clinical features of 7 patients with neurosarcoidosis manifesting as longitudinal ultra-extensive transverse myelitis. No. Age Sex Race
Symptoms and signs at onset
Prior Biopsy sarcoidosis source
Serum Location of abnormal findings radiological findings
1
55 F AA
1st episode: acute LE/UE paresthesia 2nd episode: acute LE paresthesia
None
Lung
ACE 34
2
40
1st: subacute LE paresthesia, None spastic paraparesis. 2nd: LE weakness, urinary incontinence Subacute UE/LE paresthesia, None spastic paraparesis, urinary retention Acute LE paresthesia and None. weakness, urinary retention
Lung
ACE 36, NMO (–)
Lung
ACE 10, NMO (–) ACE 24, NMO (–)
MW
1st episode: C3–T3, LME 2nd 1st episode: IVMP, episode: C4–T4, LME brain: dexamethasone, MTX 2nd episode: leflunomide, medulla, LME infliximab Maintenance: leflunomide 1st episode: T1–T8, PE 2nd 1st episode: IVMP, prednisone 2nd episode: MTX, infliximab episode: T4–12, PE Maintenance: MTX Brain: corpus callosum Cord: C2–T2, SPE at C5/6 Brain: white matter
3
39 M AA
4
57 M AA
5
42 M AA
Subacute fever, headache, hearing loss, LE weakness, urinary retention
Yes
Lymph ACE 31 node
Cord: T1–10, PE Brain: normal
6
63 F AA
Chronic LE paresthesia and weakness, urinary urgency
None
None
ACE 100
Cord: T2–7, SPE at T4/5 Brain: cortical LME
7
48FW Subacute LE paresthesia, urinary urgency
None
Lung
ACE 37 NMO (–)
Cord: C3–T4, LME, SPE Brain: normal
Lung
Immunosuppressive treatment used
Cord: C1–7, LME, PE Brain: pons and cerebral peduncle
Follow-up duration (months) and outcome 84 months. Clinical improvement. Residual LE paresthesia. MRI normalized.
123 months. Clinical improvement. Mild residual LE weakness. MRI normalized.
21 months. Clinical improvement. Mild residual LE weakness. MRI: normal cord with minimal LME. 25 months. Clinical improvement. Wheelchair bound and incontinent. MRI: residual C2–5 lesion. 6 months. Clinical improvement. Leflunomide, infliximab, IVMP, Residual LE weakness and plasmapheresis, prednisone, neurogenic bladder. MRI: residual cyclophosphamide, MTX T1–3 lesion. Maintenance: prednisone, MTX 78 months. Clinical improvement. IVMP, dexamethasone, Minimal residual LE weakness. azathioprine, infliximab, adalimumab, cyclophosphamide. MRI normalized. Maintenance: none IVMP, prednisone, azathioprine, 52 months. Clinical improvement. Residual LE paresthesia. MRI: near infliximab Maintenance: normalized. prednisone, azathioprine IVMP, prednisone, MTX, infliximab. Maintenance: MTX IVMP, prednisone, azathioprine. Maintenance: azathioprine
Abbreviations: F female, M male, AA African American, W Caucasian, LE lower extremity, UE upper extremity, ACE angiotensin converting enzyme, NMO neuromyelitis optica immunoglobulin G antibody (NMO-IgG), C cervical, T thoracic, LME leptomeningeal enhancement, PE patchy enhancement, SPE solid parenchymal enhancement, IVMP intravenous methylprednisolone, and MTX methotrexate. Normal range for serum angiotensin-converting enzyme: 3–48 unit/liter.
Biopsy findings consistent with sarcoidosis were seen in 6 patients (lung 5 and lymph node 1). In 4 (57.1%) patients, neurological symptoms attributable to myelitis were the first manifestation of sarcoidosis. A biopsy proven sarcoidosis was found in only 1 patient (patient 5) prior to the neurological presentation. Patient 5 was diagnosed with sarcoidosis via a lymph node biopsy 7 years prior, and maintained on a treatment regime of leflunomide and infliximab. In patient 4, multiple lung lesions were present for 1 year without a precise diagnosis. In patient 6, the presence of multiple lung and skin lesions led to a suspicion of sarcoidosis without a pathological diagnosis 15 years prior. In 6 (85.7%) patients, the onset of neurological symptoms was acute or subacute while the remaining patient had a chronic progressive course. Extremity paresthesia and lower extremity weakness were the most common initial symptoms, seen in 6 (85.7%) and 5 (71.4%) patients respectively. Urological symptoms secondary to neurogenic bladder were present in 3 (42.9%) patients. A monophasic course of myelitis occurred in 5 patients. In the remaining 2 patients (patients 1 and 2), recurrent myelitis affecting approximately similar spinal segments occurred following a tapering of immunotherapy (Table 1).
All patients underwent spinal MRI testing, revealing extensive and contiguous T2 signal abnormality in the cervical and/or thoracic spinal cord segments (Fig. 1). Exclusive thoracic spinal cord involvement was seen in 3 patients, exclusive cervical in 1, and combined cervical and thoracic involvement in the remaining 3. The mean number of spinal segments affected was 8 (range: 6 to 10). On axial images, lesions were preferentially located at the central or centrodorsal cord portion. Three contrast enhancement patterns were observed: intense parenchymal at the central or dorsal location in 3, nodular leptomeningeal enhancement in 4, and patchy parenchymal in 2 cases (Fig. 1). Brain MRI was performed in all patients, being normal in 2, showing leptomeningeal enhancement without parenchymal involvement in 2, and revealing scattered white matter changes in the subcortical region, corpus callosum or brainstem in the remaining 3 cases.
3.3. Laboratory findings
3.5. Treatment and prognosis
Serum angiotensin converting enzyme (ACE) level was examined in all patients, being elevated in patient 6 only. The neuromyelitis optica immunoglobulin G antibody (NMO-IgG) was negative in all 4 patients tested. Cerebrospinal fluid (CSF) protein level was increased in 6 patients, with a mean value of 105.1 mg/dl (range: 45 to 295 mg/dl). Pleocytosis was evident in all patients, with a mean white blood cell count of 134/μl (range: 6 to 648/μl). CSF glucose level ranged from 35 to 105 mg/dl, and was abnormally low in 3 patients. CSF bacterial and fungal culture was negative in all patients. ACE level was normal in the CSF of all 4 patients tested. Serum or CSF flow cytometry was normal in all cases, without immunophenotypic evidence of lymphoproliferative
Corticosteroids (methylprednisolone, prednisone or dexamethasone) were given to all patients as the initial treatment. Other used immunotherapeutic agents included infliximab (N = 6), methotrexate (N = 4), azathioprine (N = 3), leflunomide (N = 2), cyclophosphamide (N = 2), and adalimumab (N = 1). All patients improved following immunosuppressive treatment and the mean onset of improvement occurred at 1 month (range: 3 days to 3 months). Two patients with a relapsing course also improved once immunosuppressive treatments were strengthened. Residual neurological deficits were present in all patients at the study conclusion, being relatively mild in 5 patients. Two patients (patients 4 and 5) improved partially but still demonstrated
disorder such as lymphoma. Visual evoked potential (VEP) or optical coherence tomography (OCT) testing was normal in all 4 patients tested. 3.4. Radiological findings
66
L. Wang, Y. Li / Journal of the Neurological Sciences 355 (2015) 64–67
Fig. 1. MRI characteristics of longitudinal ultra-extensive transverse myelitis in patients with neurosarcoidosis. In patient 1 (A,B,C), contiguous signal abnormalities were observed in the cervical and upper thoracic cord on T2 weighted sagittal image (A), and focal solid gadolinium enhancement (arrowhead) was present on post contrast T1 weighted sequence (B). Abnormal cord signal resolved on the follow up MRI after treatment (C). In patient 7 (D, E), contiguous signal abnormalities were observed in the cervical and thoracic cord on T2 sagittal image (D), and solid enhancement was present in the dorsal cord on post contrast T1 weighted sequence (E). Other enhancement pattern observed may include a diffuse and patchy (F) or nodular leptomeningeal enhancement (G, arrow).
persistent bladder dysfunction and significant lower extremity weakness requiring assistance for ambulation. Two of 3 patients who received repeated CSF examination demonstrated persistent pleocytosis. Complete or near-complete radiographic resolution was seen in 5 patients while significant radiological improvement with residual cord signal abnormalities was seen the remaining 2 patients (patients 4 and 5) (Table 1). At the study conclusion, 5 patients were on 1 or no maintenance immunotherapy, while the remaining 2 patients were on 2 immunosuppressive agents. 4. Discussion In this case series, we summarized the presentation and clinical course of 7 patients with neurosarcoidosis presenting with LUTM. In each case, the involvement of spinal cord included 6 or more segments. A spinal cord biopsy to confirm the presence of non-caseating granulomas was not performed in any of the cases. However, the history of pulmonary sarcoidosis, combining with the clinical and radiological improvement following treatment relative specific for sarcoidosis argues strongly for spinal cord sarcoidosis being the most likely explanation for these patients. Based on the criteria proposed by Zajicek et al., all our patients fitted the criteria of probable neurosarcoidosis [7]. Our analyses of these patients with neurosarcoidosis manifesting as LUTM suggest the following: 1) the occurrence of neurological symptoms in most patients was subacute or acute; 2) the cord lesions were mostly located at the central or central–dorsal portion, affecting thoracic cord segments slightly more frequently than cervical; 3) extra-neural lesions especially those in the lung were valuable in helping diagnose these patients while serum and CSF ACE level was of limited value; and 4) despite of the presence of extensive lesion, the combinatorial usage of corticosteroids and immunosuppressive agents were effective in all cases. Only 1 patient was diagnosed as sarcoidosis and only 2 additional developed extra-neural symptoms prior to the onset of neurological symptoms. Therefore, LUTM can be the first presentation of sarcoidosis. Neurosarcoidosis should be considered in the differential diagnosis of
LUTM, and chest imaging to look for hilar adenopathy or parenchymal changes should be routinely performed. Positive findings suggestive of sarcoidosis on chest imaging were previously reported in 24 to 68% of individuals who present with neurosarcoidosis [5]. Serum and cerebrospinal ACE levels are neither specific nor sensitive for sarcoidosis with LUTM, similarly to the previous reports on patients with other subtypes of neurosarcoidosis [8]. Elevated CSF protein was seen in the majority of patients, and CSF pleocytosis was seen in all patients, similar to previously reported [9]. However, these non-specific findings are of limited value in differentiating spinal cord sarcoidosis from other forms of inflammatory myelitis. Low CSF glucose level was observed in 3 of 7 cases, as previously reported in neurosarcoidosis [1]. In the setting of negative bacterial or fungal culture results, the presence of low CSF glucose may have its unique diagnostic value for neurosarcoidosis. Finally, gadolinium enhancement on MRI was observed in every patient. The solid central and posterior parenchymal and nodular leptomeningeal enhancement seen in most cases could be helpful for differentiating spinal cord sarcoidosis from acute transverse myelitis of other etiologies, as the latter typically shows poorly defined, patchy or heterogeneous enhancement [10]. One of the most common differential diagnoses for LUTM is neuromyelitis optica (NMO) spectrum disorder. Previously, there was 1 case report describing sarcoidosis coexisting with NMO [11]. However, no episodes of optic neuritis ever occurred in any of our patients, and no subclinical optic nerve involvement was observed in any of the 4 patients undergoing VEP or OCT testing. NMO-IgG antibody was negative in all 4 patients tested. Therefore, we did not feel NMO spectrum disorder is a suitable diagnosis for our patients. There is no consensus on the best treatment for LUTM in sarcoidosis patients because of its rarity. Similar to previous reports, we found LUTM complicating sarcoidosis tends to respond to a combined use of corticosteroids and immunosuppressive agents [9]. Five of 7 patients improved significantly, with minimal or no neurological deficits. In 5 patients, there was a complete or near-complete radiographic recovery. This magnitude of recovery is quite remarkable, considering that all patients in this study demonstrated extensive spinal cord lesions involving
L. Wang, Y. Li / Journal of the Neurological Sciences 355 (2015) 64–67
multiple segments. Methotrexate and infliximab were the mostly used drugs in this group of patients. Five of 6 (83.3%) patients taking infliximab reported a marked clinical recovery, further supporting the impression that infliximab is promising in treating neurosarcoidosis, especially when being refractory to other medications [12]. Conflict of interest There are no conflict of interest for the authors. References [1] B.J. Stern, A. Krumholz, C. Johns, P. Scott, J. Nissim, Sarcoidosis and its neurological manifestations, Arch Neurol 42 (9) (1985) 909–917. [2] D.A. Bradley, E.E. Lower, R.P. Baughman, Diagnosis and management of spinal cord sarcoidosis, Sarcoidosis Vasc Diffuse Lung Dis 23 (1) (2006) 58–65. [3] S. Bolat, G. Berding, R. Dengler, M. Stangel, C. Trebst, Fluorodeoxyglucose positron emission tomography (FDG-PET) is useful in the diagnosis of neurosarcoidosis, J Neurol Sci 287 (1-2) (2009) 257–259.
67
[4] R. Dolhun, S. Sriram, Neurosarcoidosis presenting as longitudinally extensive transverse myelitis, J Clin Neurosci 16 (4) (2009) 595–597. [5] S. Pawate, H. Moses, S. Sriram, Presentations and outcomes of neurosarcoidosis: a study of 54 cases, QJM 102 (7) (2009) 449–460. [6] Transverse Myelitis Consortium Working Group, Proposed diagnostic criteria and nosology of acute transverse myelitis, Neurology 59 (4) (2002) 499–505. [7] J.P. Zajicek, N.J. Scolding, O. Foster, M. Rovaris, J. Evanson, I.F. Moseley, et al., Central nervous system sarcoidosis—diagnosis and management, QJM 92 (2) (1999) 103–117. [8] J.C. Hoyle, C. Jablonski, H.B. Newton, Neurosarcoidosis: clinical review of a disorder with challenging inpatient presentations and diagnostic considerations, Neurohospitalist 4 (2) (2014) 94–101. [9] M. Sohn, D.A. Culver, M.A. Judson, T.F. Scott, J. Tavee, K. Nozaki, Spinal cord neurosarcoidosis, Am J Med Sci 347 (3) (2014) 195–198. [10] C. Goh, P.M. Phal, P.M. Desmond, Neuroimaging in acute transverse myelitis, Neuroimaging Clin N Am 21 (4) (2011) 951–973. [11] R. Sawaya, W. Radwan, Sarcoidosis associated with neuromyelitis optica, J Clin Neurosci 20 (8) (2013) 1156–1158. [12] A.O. Lorentzen, L. Sveberg, Ø. Midtvedt, E. Kerty, K. Heuser, Overnight response to infliximab in neurosarcoidosis: a case report and review of infliximab treatment practice, Clin Neuropharmacol 37 (5) (2014) 142–148.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Longitudinal ultra-extensive transverse myelitis as a manifestation of neurosarcoidosis Lei Wang a, Yuebing Li b,⁎ a b
Department of Neurology, Second Artillery General Hospital, Beijing 100088, China Department of Neurology, Cleveland Clinic, Cleveland, OH 44195, USA
a r t i c l e
i n f o
Article history: Received 9 March 2015 Received in revised form 19 April 2015 Accepted 12 May 2015 Available online 22 May 2015 Keywords: Sarcoidosis Neurosarcoidosis Spinal cord sarcoidosis Myelopathy Transverse myelitis Immunosuppression
a b s t r a c t Objective: To analyze the clinical characteristics and outcome of patients with neurosarcoidosis manifesting as longitudinal transverse myelitis spanning 6 or more spinal segments. Method: Retrospective analysis of 7 cases from a single institution. Results: Four males and 5 African–American were included. The mean onset age for neurological symptoms was 49.1 years old. Only 1 patient had a prior diagnosis of sarcoidosis. In all patients, spinal MRI showed contiguous cervical and/or thoracic cord lesions predominantly in a central or centrodorsal location, associated with parenchymal or leptomeningeal gadolinium enhancement. Cerebral spinal fluid (CSF) pleocytosis was present in all and hypoglycorrhachia in 3 patients. Angiotensin-converting enzyme (ACE) level was elevated in the serum of 1 patient while being normal in the CSF of all 4 cases tested. Chest imaging facilitated the diagnosis of sarcoidosis in all cases. The use of corticosteroid and immunosuppressive agents including infliximab and methotrexate led to improved outcome. Conclusions: Neurosarcoidosis should be considered in the differential diagnosis of longitudinal ultra-extensive myelitis, even in the absence of previously diagnosed sarcoidosis. Timely usage of corticosteroid and immunosuppressive agents improves the clinical outcome of patients with ultra-extensive spinal cord sarcoidosis. © 2015 Elsevier B.V. All rights reserved.
1. Background Sarcoidosis is a multi-system granulomatous disorder which often affects lung, skin, liver, bone marrow and nervous system. The incidence of nervous system involvement in sarcoidosis is approximately 5 to 15% [1]. Spinal cord sarcoidosis is very rare, occurring in less than 1% of all sarcoidosis patients [2]. Longitudinal extensive transverse myelitis, defined as spinal cord inflammatory lesions extending longitudinally over 3 or more vertebral segments, was rarely reported in neurosarcoidosis [3–5]. In this study, we describe a group of 7 patients who demonstrated reversible myelitis affecting 6 or more contiguous spinal segments, termed here longitudinal ultra-extensive transverse myelitis (LUTM), as a manifestation of neurosarcoidosis.
findings, biopsy results, treatment regimens and clinical outcome. Data were expressed as mean, standard deviation and range. Percentages of positive and negative findings were calculated. No statistical analysis was needed. Positive diagnosis of transverse myelitis was confirmed using previously published criteria [6]. Acute onset was defined as neurological deficit reaching its peak within 1 month, while subacute onset between 1 and 3 months and chronic onset after 3 months or with a progressive course. Duration of follow-up included time between first and most recent neurological assessments. 3. Results 3.1. Patient demographics
2. Methods The study was approved by the Cleveland Clinic Institutional Review Board. Seven patients were included in the study. Data from electronic medical records were collected, including demographics (gender, race and onset age), symptoms and signs, laboratory and radiological
Three patients (42.9%) were female and 5 (71.4%) African American. The mean age at the onset of neurological symptoms was 49.1 ± 9.4 years (range: 39 to 63 years). The mean follow-up duration was 55.6 months (range: 6 to 123 months).The clinical summary for all 7 patients is outlined in Table 1. 3.2. Clinical presentation
⁎ Corresponding author at: Department of Neurology, Cleveland Clinic, 9500 Euclid Avenue, S90, Cleveland, OH 44195, USA. Tel.: +1 216 445 9525; fax: +1 216 445 4653. E-mail address: [email protected] (Y. Li).
http://dx.doi.org/10.1016/j.jns.2015.05.017 0022-510X/© 2015 Elsevier B.V. All rights reserved.
Chest imaging revealed pulmonary involvement in all 7 patients, manifesting predominantly as hilar and/or mediastinal node enlargement.
L. Wang, Y. Li / Journal of the Neurological Sciences 355 (2015) 64–67
65
Table 1 Clinical features of 7 patients with neurosarcoidosis manifesting as longitudinal ultra-extensive transverse myelitis. No. Age Sex Race
Symptoms and signs at onset
Prior Biopsy sarcoidosis source
Serum Location of abnormal findings radiological findings
1
55 F AA
1st episode: acute LE/UE paresthesia 2nd episode: acute LE paresthesia
None
Lung
ACE 34
2
40
1st: subacute LE paresthesia, None spastic paraparesis. 2nd: LE weakness, urinary incontinence Subacute UE/LE paresthesia, None spastic paraparesis, urinary retention Acute LE paresthesia and None. weakness, urinary retention
Lung
ACE 36, NMO (–)
Lung
ACE 10, NMO (–) ACE 24, NMO (–)
MW
1st episode: C3–T3, LME 2nd 1st episode: IVMP, episode: C4–T4, LME brain: dexamethasone, MTX 2nd episode: leflunomide, medulla, LME infliximab Maintenance: leflunomide 1st episode: T1–T8, PE 2nd 1st episode: IVMP, prednisone 2nd episode: MTX, infliximab episode: T4–12, PE Maintenance: MTX Brain: corpus callosum Cord: C2–T2, SPE at C5/6 Brain: white matter
3
39 M AA
4
57 M AA
5
42 M AA
Subacute fever, headache, hearing loss, LE weakness, urinary retention
Yes
Lymph ACE 31 node
Cord: T1–10, PE Brain: normal
6
63 F AA
Chronic LE paresthesia and weakness, urinary urgency
None
None
ACE 100
Cord: T2–7, SPE at T4/5 Brain: cortical LME
7
48FW Subacute LE paresthesia, urinary urgency
None
Lung
ACE 37 NMO (–)
Cord: C3–T4, LME, SPE Brain: normal
Lung
Immunosuppressive treatment used
Cord: C1–7, LME, PE Brain: pons and cerebral peduncle
Follow-up duration (months) and outcome 84 months. Clinical improvement. Residual LE paresthesia. MRI normalized.
123 months. Clinical improvement. Mild residual LE weakness. MRI normalized.
21 months. Clinical improvement. Mild residual LE weakness. MRI: normal cord with minimal LME. 25 months. Clinical improvement. Wheelchair bound and incontinent. MRI: residual C2–5 lesion. 6 months. Clinical improvement. Leflunomide, infliximab, IVMP, Residual LE weakness and plasmapheresis, prednisone, neurogenic bladder. MRI: residual cyclophosphamide, MTX T1–3 lesion. Maintenance: prednisone, MTX 78 months. Clinical improvement. IVMP, dexamethasone, Minimal residual LE weakness. azathioprine, infliximab, adalimumab, cyclophosphamide. MRI normalized. Maintenance: none IVMP, prednisone, azathioprine, 52 months. Clinical improvement. Residual LE paresthesia. MRI: near infliximab Maintenance: normalized. prednisone, azathioprine IVMP, prednisone, MTX, infliximab. Maintenance: MTX IVMP, prednisone, azathioprine. Maintenance: azathioprine
Abbreviations: F female, M male, AA African American, W Caucasian, LE lower extremity, UE upper extremity, ACE angiotensin converting enzyme, NMO neuromyelitis optica immunoglobulin G antibody (NMO-IgG), C cervical, T thoracic, LME leptomeningeal enhancement, PE patchy enhancement, SPE solid parenchymal enhancement, IVMP intravenous methylprednisolone, and MTX methotrexate. Normal range for serum angiotensin-converting enzyme: 3–48 unit/liter.
Biopsy findings consistent with sarcoidosis were seen in 6 patients (lung 5 and lymph node 1). In 4 (57.1%) patients, neurological symptoms attributable to myelitis were the first manifestation of sarcoidosis. A biopsy proven sarcoidosis was found in only 1 patient (patient 5) prior to the neurological presentation. Patient 5 was diagnosed with sarcoidosis via a lymph node biopsy 7 years prior, and maintained on a treatment regime of leflunomide and infliximab. In patient 4, multiple lung lesions were present for 1 year without a precise diagnosis. In patient 6, the presence of multiple lung and skin lesions led to a suspicion of sarcoidosis without a pathological diagnosis 15 years prior. In 6 (85.7%) patients, the onset of neurological symptoms was acute or subacute while the remaining patient had a chronic progressive course. Extremity paresthesia and lower extremity weakness were the most common initial symptoms, seen in 6 (85.7%) and 5 (71.4%) patients respectively. Urological symptoms secondary to neurogenic bladder were present in 3 (42.9%) patients. A monophasic course of myelitis occurred in 5 patients. In the remaining 2 patients (patients 1 and 2), recurrent myelitis affecting approximately similar spinal segments occurred following a tapering of immunotherapy (Table 1).
All patients underwent spinal MRI testing, revealing extensive and contiguous T2 signal abnormality in the cervical and/or thoracic spinal cord segments (Fig. 1). Exclusive thoracic spinal cord involvement was seen in 3 patients, exclusive cervical in 1, and combined cervical and thoracic involvement in the remaining 3. The mean number of spinal segments affected was 8 (range: 6 to 10). On axial images, lesions were preferentially located at the central or centrodorsal cord portion. Three contrast enhancement patterns were observed: intense parenchymal at the central or dorsal location in 3, nodular leptomeningeal enhancement in 4, and patchy parenchymal in 2 cases (Fig. 1). Brain MRI was performed in all patients, being normal in 2, showing leptomeningeal enhancement without parenchymal involvement in 2, and revealing scattered white matter changes in the subcortical region, corpus callosum or brainstem in the remaining 3 cases.
3.3. Laboratory findings
3.5. Treatment and prognosis
Serum angiotensin converting enzyme (ACE) level was examined in all patients, being elevated in patient 6 only. The neuromyelitis optica immunoglobulin G antibody (NMO-IgG) was negative in all 4 patients tested. Cerebrospinal fluid (CSF) protein level was increased in 6 patients, with a mean value of 105.1 mg/dl (range: 45 to 295 mg/dl). Pleocytosis was evident in all patients, with a mean white blood cell count of 134/μl (range: 6 to 648/μl). CSF glucose level ranged from 35 to 105 mg/dl, and was abnormally low in 3 patients. CSF bacterial and fungal culture was negative in all patients. ACE level was normal in the CSF of all 4 patients tested. Serum or CSF flow cytometry was normal in all cases, without immunophenotypic evidence of lymphoproliferative
Corticosteroids (methylprednisolone, prednisone or dexamethasone) were given to all patients as the initial treatment. Other used immunotherapeutic agents included infliximab (N = 6), methotrexate (N = 4), azathioprine (N = 3), leflunomide (N = 2), cyclophosphamide (N = 2), and adalimumab (N = 1). All patients improved following immunosuppressive treatment and the mean onset of improvement occurred at 1 month (range: 3 days to 3 months). Two patients with a relapsing course also improved once immunosuppressive treatments were strengthened. Residual neurological deficits were present in all patients at the study conclusion, being relatively mild in 5 patients. Two patients (patients 4 and 5) improved partially but still demonstrated
disorder such as lymphoma. Visual evoked potential (VEP) or optical coherence tomography (OCT) testing was normal in all 4 patients tested. 3.4. Radiological findings
66
L. Wang, Y. Li / Journal of the Neurological Sciences 355 (2015) 64–67
Fig. 1. MRI characteristics of longitudinal ultra-extensive transverse myelitis in patients with neurosarcoidosis. In patient 1 (A,B,C), contiguous signal abnormalities were observed in the cervical and upper thoracic cord on T2 weighted sagittal image (A), and focal solid gadolinium enhancement (arrowhead) was present on post contrast T1 weighted sequence (B). Abnormal cord signal resolved on the follow up MRI after treatment (C). In patient 7 (D, E), contiguous signal abnormalities were observed in the cervical and thoracic cord on T2 sagittal image (D), and solid enhancement was present in the dorsal cord on post contrast T1 weighted sequence (E). Other enhancement pattern observed may include a diffuse and patchy (F) or nodular leptomeningeal enhancement (G, arrow).
persistent bladder dysfunction and significant lower extremity weakness requiring assistance for ambulation. Two of 3 patients who received repeated CSF examination demonstrated persistent pleocytosis. Complete or near-complete radiographic resolution was seen in 5 patients while significant radiological improvement with residual cord signal abnormalities was seen the remaining 2 patients (patients 4 and 5) (Table 1). At the study conclusion, 5 patients were on 1 or no maintenance immunotherapy, while the remaining 2 patients were on 2 immunosuppressive agents. 4. Discussion In this case series, we summarized the presentation and clinical course of 7 patients with neurosarcoidosis presenting with LUTM. In each case, the involvement of spinal cord included 6 or more segments. A spinal cord biopsy to confirm the presence of non-caseating granulomas was not performed in any of the cases. However, the history of pulmonary sarcoidosis, combining with the clinical and radiological improvement following treatment relative specific for sarcoidosis argues strongly for spinal cord sarcoidosis being the most likely explanation for these patients. Based on the criteria proposed by Zajicek et al., all our patients fitted the criteria of probable neurosarcoidosis [7]. Our analyses of these patients with neurosarcoidosis manifesting as LUTM suggest the following: 1) the occurrence of neurological symptoms in most patients was subacute or acute; 2) the cord lesions were mostly located at the central or central–dorsal portion, affecting thoracic cord segments slightly more frequently than cervical; 3) extra-neural lesions especially those in the lung were valuable in helping diagnose these patients while serum and CSF ACE level was of limited value; and 4) despite of the presence of extensive lesion, the combinatorial usage of corticosteroids and immunosuppressive agents were effective in all cases. Only 1 patient was diagnosed as sarcoidosis and only 2 additional developed extra-neural symptoms prior to the onset of neurological symptoms. Therefore, LUTM can be the first presentation of sarcoidosis. Neurosarcoidosis should be considered in the differential diagnosis of
LUTM, and chest imaging to look for hilar adenopathy or parenchymal changes should be routinely performed. Positive findings suggestive of sarcoidosis on chest imaging were previously reported in 24 to 68% of individuals who present with neurosarcoidosis [5]. Serum and cerebrospinal ACE levels are neither specific nor sensitive for sarcoidosis with LUTM, similarly to the previous reports on patients with other subtypes of neurosarcoidosis [8]. Elevated CSF protein was seen in the majority of patients, and CSF pleocytosis was seen in all patients, similar to previously reported [9]. However, these non-specific findings are of limited value in differentiating spinal cord sarcoidosis from other forms of inflammatory myelitis. Low CSF glucose level was observed in 3 of 7 cases, as previously reported in neurosarcoidosis [1]. In the setting of negative bacterial or fungal culture results, the presence of low CSF glucose may have its unique diagnostic value for neurosarcoidosis. Finally, gadolinium enhancement on MRI was observed in every patient. The solid central and posterior parenchymal and nodular leptomeningeal enhancement seen in most cases could be helpful for differentiating spinal cord sarcoidosis from acute transverse myelitis of other etiologies, as the latter typically shows poorly defined, patchy or heterogeneous enhancement [10]. One of the most common differential diagnoses for LUTM is neuromyelitis optica (NMO) spectrum disorder. Previously, there was 1 case report describing sarcoidosis coexisting with NMO [11]. However, no episodes of optic neuritis ever occurred in any of our patients, and no subclinical optic nerve involvement was observed in any of the 4 patients undergoing VEP or OCT testing. NMO-IgG antibody was negative in all 4 patients tested. Therefore, we did not feel NMO spectrum disorder is a suitable diagnosis for our patients. There is no consensus on the best treatment for LUTM in sarcoidosis patients because of its rarity. Similar to previous reports, we found LUTM complicating sarcoidosis tends to respond to a combined use of corticosteroids and immunosuppressive agents [9]. Five of 7 patients improved significantly, with minimal or no neurological deficits. In 5 patients, there was a complete or near-complete radiographic recovery. This magnitude of recovery is quite remarkable, considering that all patients in this study demonstrated extensive spinal cord lesions involving
L. Wang, Y. Li / Journal of the Neurological Sciences 355 (2015) 64–67
multiple segments. Methotrexate and infliximab were the mostly used drugs in this group of patients. Five of 6 (83.3%) patients taking infliximab reported a marked clinical recovery, further supporting the impression that infliximab is promising in treating neurosarcoidosis, especially when being refractory to other medications [12]. Conflict of interest There are no conflict of interest for the authors. References [1] B.J. Stern, A. Krumholz, C. Johns, P. Scott, J. Nissim, Sarcoidosis and its neurological manifestations, Arch Neurol 42 (9) (1985) 909–917. [2] D.A. Bradley, E.E. Lower, R.P. Baughman, Diagnosis and management of spinal cord sarcoidosis, Sarcoidosis Vasc Diffuse Lung Dis 23 (1) (2006) 58–65. [3] S. Bolat, G. Berding, R. Dengler, M. Stangel, C. Trebst, Fluorodeoxyglucose positron emission tomography (FDG-PET) is useful in the diagnosis of neurosarcoidosis, J Neurol Sci 287 (1-2) (2009) 257–259.
67
[4] R. Dolhun, S. Sriram, Neurosarcoidosis presenting as longitudinally extensive transverse myelitis, J Clin Neurosci 16 (4) (2009) 595–597. [5] S. Pawate, H. Moses, S. Sriram, Presentations and outcomes of neurosarcoidosis: a study of 54 cases, QJM 102 (7) (2009) 449–460. [6] Transverse Myelitis Consortium Working Group, Proposed diagnostic criteria and nosology of acute transverse myelitis, Neurology 59 (4) (2002) 499–505. [7] J.P. Zajicek, N.J. Scolding, O. Foster, M. Rovaris, J. Evanson, I.F. Moseley, et al., Central nervous system sarcoidosis—diagnosis and management, QJM 92 (2) (1999) 103–117. [8] J.C. Hoyle, C. Jablonski, H.B. Newton, Neurosarcoidosis: clinical review of a disorder with challenging inpatient presentations and diagnostic considerations, Neurohospitalist 4 (2) (2014) 94–101. [9] M. Sohn, D.A. Culver, M.A. Judson, T.F. Scott, J. Tavee, K. Nozaki, Spinal cord neurosarcoidosis, Am J Med Sci 347 (3) (2014) 195–198. [10] C. Goh, P.M. Phal, P.M. Desmond, Neuroimaging in acute transverse myelitis, Neuroimaging Clin N Am 21 (4) (2011) 951–973. [11] R. Sawaya, W. Radwan, Sarcoidosis associated with neuromyelitis optica, J Clin Neurosci 20 (8) (2013) 1156–1158. [12] A.O. Lorentzen, L. Sveberg, Ø. Midtvedt, E. Kerty, K. Heuser, Overnight response to infliximab in neurosarcoidosis: a case report and review of infliximab treatment practice, Clin Neuropharmacol 37 (5) (2014) 142–148.
